13-24434601-G-T

Variant names:

• chr13-24434601-G-T
• NM_006437.4:c.4540C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006437.4(PARP4):​c.4540C>A​(p.Pro1514Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PARP4 NM_006437.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.30

Genes affected

PARP4 (HGNC:271): (poly(ADP-ribose) polymerase family member 4) This gene encodes poly(ADP-ribosyl)transferase-like 1 protein, which is capable of catalyzing a poly(ADP-ribosyl)ation reaction. This protein has a catalytic domain which is homologous to that of poly (ADP-ribosyl) transferase, but lacks an N-terminal DNA binding domain which activates the C-terminal catalytic domain of poly (ADP-ribosyl) transferase. Since this protein is not capable of binding DNA directly, its transferase activity may be activated by other factors such as protein-protein interaction mediated by the extensive carboxyl terminus. [provided by RefSeq, Jul 2008]

TPTE2P6 (HGNC:42644): (TPTE2 pseudogene 6)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058227032).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARP4	NM_006437.4	c.4540C>A	p.Pro1514Thr	missense_variant	Exon 31 of 34	ENST00000381989.4	NP_006428.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARP4	ENST00000381989.4	c.4540C>A	p.Pro1514Thr	missense_variant	Exon 31 of 34	1	NM_006437.4	ENSP00000371419.3
TPTE2P6	ENST00000445572.5	n.233+25297G>T		intron_variant	Intron 3 of 9	6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4540C>A (p.P1514T) alteration is located in exon 31 (coding exon 30) of the PARP4 gene. This alteration results from a C to A substitution at nucleotide position 4540, causing the proline (P) at amino acid position 1514 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.036
DANN	Benign	0.51
DEOGEN2	Benign	0.038	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.00092	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.55	N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.021
Sift	Benign	0.20	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.072
MutPred		0.34		Gain of catalytic residue at Q1519 (P = 0.0019);
MVP		0.26
MPC		0.13
ClinPred		0.14	T
GERP RS		-4.2
Varity_R		0.031
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-25008739;